Unexpected products from the formylation of N,N-dimethylanilines with 2-formamidopyridine in POCl3

Article abstract of DOI:10.1039/b006148o

The formation of unexpected products from the formylation of N,N-dimethylanilines with 2-formamidopyridine in POCl₃ was discussed. The reaction led to the formation of a product derived from two units of the t-aniline and one of the pyridine with less four protons. The formation of these products was due to the oxidation of one of the methyl groups of an N,N-dimethyl-aniline moiety, a process which is initiated by a 't-amino effect' interaction.

Full text of DOI:10.1039/b006148o

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Unexpected products from the formylation of N,N-dimethylanilines
with 2-formamidopyridine in POCl3
Ying Cheng,*a Peng Jiao,a David J. Williamsb and Otto-Meth Cohn*c
1
a Chemistry Department, Beijing Normal University, Beijing 100875, China.
E-mail: Yincheng@public2.east.net.cn
b Chemistry Department Imperial College, London, UK SW7 2AY
c Chemistry Department, University of Sunderland, Sunderland, UK SR1 3SD.
E-mail: Otto.meth-cohn@sunderland.ac.uk
Received (in Cambridge, UK) 31st July 2000, Accepted 1st November 2000
First published as an Advance Article on the web 11th December 2000
2-Formamidopyridine in POCl3 solution reacts with N,N-dimethylaniline to give tris(4-dimethylaminophenyl)-
methane in 80% yield but with 4-X-N,N-dimethylanilines it gives 2-dimethylamino-5-X-phenyl[2-(N-methyl)-
formamido-5-X-phenyl](2-pyridylamino)methanes.
Introduction
Formanilide in the presence of POCl3 was first used as a
formylating agent by Dimroth and Zoeppritz in 19021 who
employed it to formylate resorcinol. However it failed to
formylate N,N-dimethylaniline. Similar results were reported
by Johnson and Lane,2 Pratt and Robinson,3 Froeschl and
Bomberg,4 Nenitzescu and Isacescu5 and Oesterlin6 who were
able to formylate related highly activated systems with this
Scheme 1
combination. The limitations of formanilide as the formylating
amide led to the discovery by Vilsmeier and Haack of the
ano-5,6,11,12-tetrahydrodibenzo[b, f ][1,5]diazocine), might be
accessible by the use of a formanilide as the Vilsmeier amide.
Furthermore, 2-formamidopyridine should be
formylator than formanilide itself, especially if N-protonated or
excellent reagent, N-methylformanilide.7 From then on, the
Vilsmeier’s reaction has been extensively studied and more
recently, widely used in the preparation of heterocyclic com-
pounds.8 In earlier work, we demonstrated that the Vilsmeier
reagents derived from N-methylformanilides 1 and POCl3,9
a stronger
acylated.
10
or from 2-(N-methyl)formamidopyridine 2 and (COCl)2
reacted with 4-substituted dimethylanilines 3 to afford N,NЈ-
dimethyl-5,6,11,12-tetrahydrodibenzo[b, f ][1,5]diazocines 4 or
Results and discussion
In fact, formanilides proved ineffective agents as indicated
above. We therefore reacted 2-formamidopyridine with various
para-substituted N,N-dimethylanilines in POCl3 solution.
Surprisingly, the reaction took a totally different course leading
to a product derived from two units of the t-aniline and one of
the pyridine, less four protons, as indicated by mass spectral
and CHN analytical data. The infrared and NMR spectra were
insufficient to put the structure beyond doubt and the structure
7 (X = Cl) was established by X-ray crystallography for the
product from 4-chloro-N,N-dimethylaniline, as shown in Fig. 1
Further examples are tabulated in Scheme 2, the yields being
based upon the optimal use of 1:2 mol of aniline to pyridine
reactant respectively. Full details of conditions, yields and
N,NЈ-dimethyl-5,6,11,12-tetrahydrobenzo[ f ]pyrido[2,3-b][1,5]-
diazocines 5 respectively, by way of the ‘t-amino effect’11
(Scheme 1). We considered that the N-unsubstituted [1,5]diazo-
cines, which could be useful intermediates for the preparation
of unsymmetrical Tröger’s bases (Tröger’s base is 5,11-meth-
Scheme 2
44
J. Chem. Soc., Perkin Trans. 1, 2001, 44–46
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b006148o

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Table 2 Melting points and elemental analysis of compounds 7 and 8
Compound
Mp/ЊC
CHN%
7a
7b
7c
7d
7e
8
152–153
153–154
169–171
195–197
182–184
177–179a
C, 74.51; H, 7.33; N, 14.29. C24H28N4O
requires C, 74.20; H 7.26; N, 14.42
C, 68.63; H, 6.96; N, 13.16. C24H28N4O3
requires C, 68.55; H, 6.71; N, 13.32
C, 66.59; H, 5.46; N, 14.02. C22H22F2N4O
requires C, 66.48; H, 5.83; N, 14.10
C, 61.52; H, 5.14; N, 12.82. C22H22Cl2N4O
requires C, 61.40; H, 5.38; N, 13.02
C, 51.27; H, 4.41; N, 10.55. C22H22Br2N4O
requires C, 50.99; H, 4.28; N, 10.81
a Lit.15 mp 177–178 ЊC.
course yielding tris(4-dimethylaminophenyl)methane
8 in
high yield (80%). This well known compound, the precursor to
‘Crystal Violet’ (the tritylium salt thereof), has in fact been
formed by, for example, the interaction of 4-dimethylamino-
benzaldehyde with N,N-dimethylaniline and an acid13 or by
treatment of a 4,4Ј-bis(dimethylamino)benzhydryl† derivative
with N,N-dimethylaniline under acid catalysis.14 Similar
benzaldehyde (i.e. an iminium salt derivative) and benzhydryl
analogues can be easily formed in our case to account for this
efficient reaction. It is of interest that while classical Vilsmeier
reagents with N,N-dimethylaniline yield solely 4-formyldi-
methylaniline, this reagent proceeds further, due to the greater
formylating ability of the derived iminium ion (cf. Scheme 3).
When the iminium intermediate of the formylation of N,N-
Fig. 1 the X-ray structure of 7 (X = Cl).12 The principal intermol-
ecular interaction is an N–H ؒ ؒ ؒ O hydrogen bond between N(14) in one
molecule and O(24) in the next [N ؒ ؒ ؒ O, H ؒ ؒ ؒ O distances 2.97, 2.27 Å,
N–H ؒ ؒ ؒ O angle 134Њ]. This interaction is supplemented by a weaker
C–H ؒ ؒ ؒ π interaction between C(10)–H in one molecule and the C(15)
pyridyl ring of another [H ؒ ؒ ؒ π distance 2.82 Å, C–H ؒ ؒ ؒ π angle 151Њ].
Table 1 Reaction conditions and results
Yields (%)
Ratio
Temp./
3 X =
of 3:6
Time/h
ЊC
7
8
Me
Me
Me
Me
Me
OMe
OMe
OMe
F
F
Cl
Cl
Br
2:1
2:1
2:1
1:1
1:2
2:1
2:1
1:2
1:1
1:2
2:1
1:2
2:1
1:1
1:2
1:2
2:1
8
20
17
18
18
17
8
18
36
18
18
18
19
18
18
15
18
80
75
94
96
96
94
100
94
90
90
90
96
90
90
94
96
90
—
—
25
47a
57
35
32
42
44
71
34
31
17
29
48
68
Br
Br
Br
H
80
a Under N2.
spectral data are recorded in Tables 1–3. Clearly, the
2-formamidopyridine is indeed a more powerful formylator
than formanilide.
The formation of these surprising products involves an
oxidation of one of the methyl groups of an N,N-dimethyl-
aniline moiety, a process that we propose is initiated by a
‘t-amino effect’ interaction. A possible pathway is illustrated in
Scheme 3. In fact, the reaction appears to require aerial oxid-
ation for optimal yields. Nevertheless it does proceed under
nitrogen. As noted in earlier work10 it is probable that iminium
intermediates behave as dehydrogenating agents and hence
the need for an excess of the pyridine amide. Addition of an
oxidant, e.g. copper() acetate, does not improve yields.
When N,N-dimethylaniline itself was treated with 2-form-
amidopyridine in POCl3 solution the reaction took a different
Scheme 3
† The IUPAC name for benzhydryl is diphenylmethyl.
J. Chem. Soc., Perkin Trans. 1, 2001, 44–46
45

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Table 3 Spectroscopic data of compounds 7 and 8
Cmpd.
IR (KBr) ν/cmϪ1
1H NMR (CDCl3) δ
13C NMR (CDCl3) δ
MS m/z (%)
7a
3280, 1660, 1600, 1480
8.05 (1H, d, J 4.2, CHO), 6.87–7.41 (7H, 161.8, 157.7, 149.9, 147.5, 134 (62), 222 (56), 235 (62), 294
m), 6.57(1H, dd, J 5.4 and 2.7), 6.38 (1H, 142.0, 137.7, 137.2, 136.4, (100), 388 (85, Mϩ), 389 (24)
d, J 8.1), 6.22 (1H, d, J 8.1), 5.04 (1H, d, J 132.1, 128.7, 128.4, 128.2,
8.1, NH), 3.02 (3H, br s, NCH3), 2.67 128.1, 128.0, 120.1, 111.9,
(1H, s, NCH), 2.54 (6H, s, 2NCH3), 2.33
(3H, s, ArCH3), 2.21 (3H, s, ArCH3)
8.0 (1H, d, J 4.8 CHO), 7.47 (1H, t, J 8.4),
7.17 (1H, d, J 8.7), 6.70–7.08 (5H, m),
6.63 (1H, t, J 5.7), 6.41 (1H, t, J 6.8), 6.34
108.7, 48.3, 44.7, 32.3, 20.9,
20.6
163.2, 162.6, 159.7, 156.5, 254 (58), 267 (70), 268 (54), 326
145.8, 142.1, 139.2, 137.7, (100), 420 (51, Mϩ), 421 (17)
137.1, 133.1, 130.3, 122.5,
7b
3380, 3260, 1680, 1600,
1500, 1480
(1H, d, J 8.5), 5.90 (1H, br s, NH), 3.76 113.9, 113.3, 113.2, 112.8,
(3H, s, OCH3), 3.71 (3H, s, OCH3), 3.06 112.7, 107.2, 55.7, 51.1,
(3H, br s, NCH3), 2.64 (1H, s, NCH), 2.50
(6H, s, 2NCH3)
8.01 (1H, d, J 4.7, CHO), 7.42 (1H, t, J 164.2, 157.8, 156.8, 148.7, 124 (56), 136 (54), 138 (56), 230
7.2), 6.94–7.27 (5H, m), 6.79 (1H, dd, J 147.9, 138.4/138.3, 138.0,
9.3 and 2.9), 6.64 (1H, t, J 5.5), 6.50 (1H, 131.0/130.9, 122.8/122.7,
d, J 6.4), 6.31 (1H, d, J 8.3), 5.27 (1H, d, J 115.6, 115.4, 115.3, 115.1,
6.3, NH), 3.07 (3H, s, NCH3), 2.65 (1H, s, 114.8, 114.5, 113.9, 113.5,
NCH), 2.54 (6H, s, 2NCH3)
8.05 (1H, d, J 5.4, CHO), 7.52 (1H, d, J
2.7), 6.98–7.44 (6H, m), 6.62 (1H, dd, J
45.8, 33.4, 30.8
7c
7d
3300, 1680, 1620, 1500,
1480
(100), 243 (58), 302 (68), 396
(50, Mϩ), 397 (13)
107.0, 50.5, 45.5, 33.1
3280, 1660, 1600, 1480
162.1, 157.4, 151.6, 147.9, 154 (61), 246 (100), 334 (64),
144.3, 139.4, 138.9, 137.2, 428 (53)/430 (34)/432 (6) (Mϩ)
8.1 and 5.4), 6.52 (1H, d, J 8.1), 6.32 (1H, 133.1, 131.0, 128.4, 128.3,
d, J 8.1), 4.92 (1H, d, J 5.4, NH), 3.03
(3H, s, NCH3), 2.67 (1H, s, NCH), 2.58
(6H, s, 2NCH3)
8.03 (1H, d, J 4.8, CHO), 6.95–7.67 (7H,
m), 6.65 (1H, t, J 5.6), 6.49 (1H, d, J 6.5),
6.25 (1H, d, J 6.0), 5.35 (1H, br s, NH),
3.03 (3H, s, NCH3), 2.67 (1H, s, NCH),
2.57 (6H, s, 2NCH3)
128.2, 127.7, 127.5, 122.7,
113.0, 109.3, 48.7, 44.6, 32.7
7e
8
3300, 1680, 1610, 1490
1620, 1530
117 (99), 290 (100), 292 (88),
405 (54), 407 (46), 424 (77),
516 (27)/518 (52)/520 (25) (Mϩ)
7.03 (6H, d, J 8.4), 6.91 (6H, d, J 7.7),
5.37 (1H, s, CH), 2.98 (18H, s, 6NCH3)
252 (65), 253 (100), 254 (20),
372 (44), 373 (96, Mϩ), 374 (26)
atography followed by recrystallisation from ethyl acetate–light
petroleum.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China.
References
1 O. Dimroth and R. Zoeppritz, Chem. Ber., 1902, 35, 994.
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dimethylaniline with DMF–POCl3 is reacted with further
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7 A. Vilsmeier and A. Haack, Chem. Ber., 1927, 60, 119.
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Experimental
Melting points are uncorrected. 1H NMR and 13C NMR
spectra in CDCl3 were obtained on Varian Unity 200 and 300
spectrometers. IR spectra were recorded using a Perkin-Elmer
782 spectrometer and mass spectra were recorded on a KYKY-
ZHT-5 instrument. Elemental analyses were performed on
a GMBH Vario EL instrument. Light petroleum refers to bp
60–80 ЊC.
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space group P21/c (no. 14), a = 9.667(3), b = 14.060(2), c = 17.366(3)
Å, β = 105.90(2)Њ, V = 2270.0(8) Å3, Z = 4, Dc = 1.256 g cmϪ3, µ(Cu-
Kα) = 27.3 cmϪ1
, F(000) = 896, T = 293 K; colourless blocks,
2-Dimethylamino-5-X-phenyl[2-N-(methyl)formamido-5-X-
phenyl](2-pyridylamino)methane 7
0.33 × 0.30 × 0.17 mm, Siemens P4/PC diffractometer, ω-scans,
3555 independent reflections. The structure was solved by direct
methods and the non-hydrogen atoms were refined anisotropically
using full matrix least-squares based on F2 to give R1 = 0.058,
wR2 = 0.151 for 2771 independent observed absorption corrected
reflections [|Fo| > 4σ(|Fo|), 2θ ≤ 124Њ] and 270 parameters. CCDC
reference number 207/497. See http://www.rsc.org/suppdata/p1/b0/
b006148o/ for crystallographic files in .cif format.
General procedure for the formylation of N,N-dimethyl-
anilines. 2-Formamidopyridine (0.02 mol) in POCl3 (10 ml) was
warmed at 80 ЊC for 2 h with stirring to form a green mixture.
To this solution, cooled in an ice-bath, was slowly added
a dimethylaniline 3 (0.01 mol). The mixture was heated at
90–100 ЊC for a period of time (see Table 1), and then poured
into ice (100 g). The aqueous solution was basified to pH ~ 8
with 10% NaOH and extracted with CHCl3 (3 × 100 ml).
The extract was dried with MgSO4 and after removal of
solvent, the products were isolated by silica gel column chrom-
13 Z.-H. Zhang, F. Yang, T.-S. Li and C.-G. Fu, Synth. Commun., 1997,
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14 H. J. Schneider, T. Schiestel and P. Zimmermann, J. Am. Chem. Soc.,
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15 M. Tsujimoto, H. Akahori, K. Hasegawa and M. Asano, PCT Int.
Appl. WO 8303840, 1983 (Chem. Abstr. 1984, 100, 69872m).
46
J. Chem. Soc., Perkin Trans. 1, 2001, 44–46